# Regulation of Dendrite Homeostasis by PINK1 and PKA in Models of Parkinson's Disease

> **NIH NIH R01** · UNIVERSITY OF NEVADA RENO · 2022 · $209,499

## Abstract

Project Summary
 Mutations in PTEN-induced kinase 1 (PINK1), a large atypical serine/threonine kinase, are associated with
juvenile-onset, autosomal recessive forms of Parkinson’s disease (PD). Full-length PINK1 is proteolytically
processed to lower molecular weight forms (c-PINK1) which are exported to the cytosol to regulate critical
neuronal functions including dendrite outgrowth, mitochondrial trafficking and survival. Published and on-
going preliminary in vitro and in vivo data supported by the parent grant (NS105783-03) show that c-PINK1
modulates downstream PKA activity and upregulates the levels of Brain-Derived Neurotrophic Factor (BDNF).
Conversely, midbrain and cortical neurons from PINK1 knockout (PINK1-KO) mice show impaired PKA
activity, decreased level of BDNF and loss of mitochondria in dendrites. Like PD, Alzheimer’s disease (AD) is
characterized by mitochondrial dysfunction, increased oxidative stress, decreased neuroprotective PKA activity
and neurotrophic support regulated by BDNF. Prior work from other research groups demonstrated that loss of
full-length PINK1 function worsens AD neuropathology including β amyloid deposition, accelerates the loss of
cortical and hippocampal neurons in a mouse model of AD. In addition, unpublished preliminary data
garnered from our research group suggests that that enhancing the levels of c-PINK1 can protect against the
loss of dendrites and mitochondrial fragmentation in the β amyloid cell culture model of AD. Collectively,
these data support a premise that c-PINK1 confers neuroprotection in models of AD by enhancing PKA and
BDNF signaling. The proposed project is relevant to AD as the goal is to determine the molecular mechanisms
by which the c-PINK1-PKA-BDNF signaling axis mitigates neurodegeneration and protects mitochondrial
structure/function in primary neurons in a cell culture model of AD. For aim 1, the molecular mechanisms by
which c-PINK1 protects dendrites and suppresses apoptosis will be analyzed by using immunohistochemical
and molecular biology approaches, and specifically test the hypothesis that c-PINK1 confers neuroprotection by
restoring PKA signaling and BDNF in primary cortical and hippocampal in an AD model. In addition, we will
test the extent that loss of PINK1 levels in vivo leads to reduced PKA and BDNF level in the hippocampus and
cortex. For aim 2, the molecular mechanisms by which c-PINK1 protects mitochondrial structure and function
will be analyzed by performing mitochondrial respiration assays and immunohistochemistry. Our research
group is well qualified to study neurodegeneration in AD models as published (Das Banerjee et al., 2021,
Molecular Neurobiology). Overall, the proposed AD-focused administrative research activities represent an
extension of current peer-reviewed research activities of the parent grant to address a critical gap in our
understanding of how cPINK1 modulates downstream PKA-BDNF to mediate dendrite homeostasis in AD
models. The data gain...

## Key facts

- **NIH application ID:** 10498719
- **Project number:** 3R01NS105783-05S2
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** RUBEN K DAGDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $209,499
- **Award type:** 3
- **Project period:** 2018-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498719

## Citation

> US National Institutes of Health, RePORTER application 10498719, Regulation of Dendrite Homeostasis by PINK1 and PKA in Models of Parkinson's Disease (3R01NS105783-05S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10498719. Licensed CC0.

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